Knockdown of RNF2 induces apoptosis by regulating MDM2 and p53 stability View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2013-01-14

AUTHORS

W Wen, C Peng, M O Kim, C Ho Jeong, F Zhu, K Yao, T Zykova, W Ma, A Carper, A Langfald, A M Bode, Z Dong

ABSTRACT

RNF2, also known as Ring1B/Ring2, is a component of the polycomb repression complex 1. RNF2 is highly expressed in many tumors, suggesting that it might have an oncogenic function, but the mechanism is unknown. Here, we show that knockdown of RNF2 significantly inhibits both cell proliferation and colony formation in soft agar, and induces apoptosis in cancer cells. Knockdown of RNF2 in HCT116 p53+/+ cells resulted in significantly more apoptosis than was observed in RNF2 knockdown HCT116 p53−/− cells, indicating that RNF2 knockdown-induced apoptosis is partially dependent on p53. Various p53-targeted genes were increased in RNF2 knockdown cells. Further studies revealed that in RNF2 knockdown cells, the p53 protein level was increased, the half-life of p53 was prolonged and p53 ubiquitination was decreased. In contrast, cells overexpressing RNF2 showed a decreased p53 protein level, a shorter p53 half-life and increased p53 ubiquitination. Importantly, we found that RNF2 directly binds with both p53 and MDM2 and promotes MDM2-mediated p53 ubiquitination. RNF2 overexpression could also increase the half-life of MDM2 and inhibit its ubiquitination. The regulation on p53 and MDM2 stability by RNF2 was also observed during the etoposide-induced DNA damage response. These results provide a possible mechanism explaining the oncogenic function of RNF2, and because RNF2 is important for cancer cell survival and proliferation, it might be an ideal target for cancer therapy or prevention. More... »

PAGES

421-428

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/onc.2012.605

DOI

http://dx.doi.org/10.1038/onc.2012.605

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1007930899

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/23318437


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33 schema:description RNF2, also known as Ring1B/Ring2, is a component of the polycomb repression complex 1. RNF2 is highly expressed in many tumors, suggesting that it might have an oncogenic function, but the mechanism is unknown. Here, we show that knockdown of RNF2 significantly inhibits both cell proliferation and colony formation in soft agar, and induces apoptosis in cancer cells. Knockdown of RNF2 in HCT116 p53+/+ cells resulted in significantly more apoptosis than was observed in RNF2 knockdown HCT116 p53−/− cells, indicating that RNF2 knockdown-induced apoptosis is partially dependent on p53. Various p53-targeted genes were increased in RNF2 knockdown cells. Further studies revealed that in RNF2 knockdown cells, the p53 protein level was increased, the half-life of p53 was prolonged and p53 ubiquitination was decreased. In contrast, cells overexpressing RNF2 showed a decreased p53 protein level, a shorter p53 half-life and increased p53 ubiquitination. Importantly, we found that RNF2 directly binds with both p53 and MDM2 and promotes MDM2-mediated p53 ubiquitination. RNF2 overexpression could also increase the half-life of MDM2 and inhibit its ubiquitination. The regulation on p53 and MDM2 stability by RNF2 was also observed during the etoposide-induced DNA damage response. These results provide a possible mechanism explaining the oncogenic function of RNF2, and because RNF2 is important for cancer cell survival and proliferation, it might be an ideal target for cancer therapy or prevention.
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40 Further studies
41 HCT116
42 MDM2
43 Mdm2 stability
44 Polycomb repression
45 RING2
46 RNF2
47 RNF2 overexpression
48 agar
49 apoptosis
50 cancer cell survival
51 cancer cells
52 cancer therapy
53 cell proliferation
54 cell survival
55 cells
56 colony formation
57 components
58 contrast
59 damage response
60 formation
61 function
62 genes
63 ideal target
64 knockdown
65 knockdown cells
66 knockdown of RNF2
67 levels
68 mechanism
69 more apoptosis
70 oncogenic function
71 overexpression
72 p53
73 p53 protein levels
74 p53 stability
75 p53 target genes
76 p53 ubiquitination
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78 prevention
79 proliferation
80 protein levels
81 regulation
82 repression
83 response
84 results
85 soft agar
86 stability
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88 survival
89 target
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91 tumors
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